Abstract Recent advances in understanding progression to castration-resistant prostate cancer (CRPC) has led to development of therapeutics that slightly increase overall survival; however, the majority of patients with CRPC succumb to disease within 2-3 years, indicating the need for metrics of precision medicine, and development of additional therapeutics. Here, we propose an ambitious approach to stratify and enhance treatment for metastatic CRPC to improve therapeutic outcomes, based on cell cycle alterations that we recently discovered. The studies described will explore untouched territory with regard to PCa targeted therapy based management, and will provide the first assessment of treatment based on subtyping in this disease context. Moreover, the studies described could provide the first biomarker with which to stratify prostate cancer treatment, and to improve therapy for patients with advanced disease. Our collective findings strongly suggest that alterations in the RB-cyclin D1/CDK4 axis play major roles in disease progression, and molecular investigation of these alterations provide a rational basis for disease stratification and improved management of advanced PCa. This postulate will be challenged in carefully planned specific aim. First, building on 2 funded clinical trials, we will use biopsy material, novel models of disease, and co-clinical trials to challenge the hypothesis that the RB-cyclin D1/CDK4 axis can be developed as biomarkers of response and as metrics for treatment stratification (Aim 1). These studies have the potential for near-term patient benefit, and could identify the first biomarker for personalized medicine in advanced PCa. Second, robust models will be used to interrogate the molecular basis of responsiveness to therapeutic directed toward alterations in RB and/or cyclin D1 status (Aim 2). Studies planned will provide critical information as to specificity and clinical placement of RB and cyclin D1- alteration dependent interventions. Finally, targeting the Rb-cyclin D1/CDK4 axis forces reliance of tumor cells on G2/M cyclin dependent kinases?plans were thereby developed to leverage this cell cycle dependence, with a goal toward discovery of new means to maximize efficacy of treatment for cells with RB-cyclin D1/CDK4 alterations (Aim 3). These collective aims build off the unique collaboration amongst a leader in clinical management of advanced PCa and a pioneer of novel clinical trials (Dr. Kelly), and a leading AR biologist with significant expertise in studying cell cycle regulation and PCa-associated cell cycle alterations (Dr. Knudsen), and an expert in clinical targeting of cell cycle alterations (Dr. O?Dwyer). As proposed, this project has the capacity to illuminate the means by which perturbations Rb-cyclin D1 alterations alter disease progression and therapeutic response in human disease, and to dramatically alter PCa management.